Vitamin A is essential for the growth, health and life of all mammals and is required for vision, reproduction and the maintenance of differentiated epithelia in skin and mucous membranes. The naturally occurring form of Vitamin A is retinol which is a free alcohol having a chemical structure described as 3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraen-1-o l. Retinol can be readily esterified with palmitic or acetic acids (or other fatty acids) to form the esters retinyl palmitate or retinyl acetate, respectively.
Retinol and its esters have been employed for many decades both internally dietary supplements and topically in dermatological products, including baby products, eye makeup remover, hair products, general cosmetics, e.g., conditioners, sprays, rinses, shampoos, tonics, skin creams, blushers, face powders, makeup bases and foundations, lipstick, nail creams and lotions, and suntan products, e.g., gels, creams, and liquids (See J. Am. Coll. of. Toxicol. 6, No. 3, pp. 282-283, 1987). In all, retinol and retinyl palmitate have been employed in approximately 240 different formulations. The 13th Report of the Cosmetic Ingredient Review as published in the Journal of the American College of Toxicology, Vol. 6, No. 3, 1987, states, in summary, that "retinyl palmitate and retinol are safe as cosmetic ingredients in the present practices of use and concentration".
More recently, acidic derivatives of retinol have been introduced which are highly effective in the treatment of severe (cystic) forms of acne. All-trans-retinoic acid, also called tretinoin, is distributed by the Ortho Division of Johnson & Johnson (New Brunswick, N.J.) under the brand name RETIN-A.RTM., which is available in cream, gel, or liquid form and is intended for topical application only. 13-cis-Retinoic acid, also called isotretinoin, is marketed under the brand name ACCUTANE.RTM. and is available in soft gelatin capsules for internal use from Roche Laboratories (Nutley, N.J.).
Other acidic derivatives of retinol are useful, e.g., for the treatment of severe cases of psoriasis. Such derivatives include Tegison.RTM. (Etretinate, Roche Laboratories, Nutley, N.J.) and Fenretinide (McNeil Pharmaceuticals, Spring House, Pa.).
The use of all-trans-retinoic acid for the topical treatment of acne is disclosed in U.S. Pat. No. 3,729,568, issued Apr. 24, 1983 to Kligman. In addition, the use of Vitamin A (retinoic acid) to retard aging effects in skin are disclosed in U.S. Pat. No. 4,603,146, issued Jul. 29, 1986, also to Kligman. An acne cream emulsion of tretinoin, i.e., all trans-retinoic acid, which is stabilized by xanthan gum, is also disclosed in U.S. Pat. No. 3,906,108, issued Sep. 16, 1975 to Felty. Tretinoin has been reported to be effective for the treatment of photoaged skin as reported in the Journal of the American Medical Association, Vol. 295, No. 4, Jan. 22/29, 1988.
While encouraging results have been obtained with these acidic retinoids, the toxic side effects can be very serious. Accutane.RTM. has given rise to extensive birth defects in children of women treated with the drug during pregnancy. Allergic responses have also been reported. Retin-A.RTM. has also been known to produce severe skin irritation, sensitization and allergic responses. Retin-A.RTM. has also given rise to abnormalities in rat and rabbit fetuses subsequent to topical administration of the compound to the mother. Thus, Retin-A.RTM. should be used during pregnancy only if clearly needed. Both of these products should be used only under the direct supervision of a physician.
Since the discovery of the acidic retinoids, an intensive search has been underway for a retinoid which provides the beneficial attributes of tretinoin and isotretinoin without their toxic side effects.